Focal changes in alpha oscillations during short-term memorization of pain: a high-density electroencephalogram study with source localization.

Memories of painful events constitute the basis for assessing patients' pain. This study explores the brain oscillatory activity during short-term memorization of a nociceptive stimulus. High-density EEG activity (128 electrodes) was recorded in 13 healthy subjects during a match-to-sample sensory discrimination task, whereby participants compared the intensity of a thumb-located electric shock (S2) with a prior stimulus to the same location (S1) delivered 8-10 s earlier. Stimuli were above or below the individual nociceptive threshold. EEG activity with intracortical source localization via LORETA source reconstruction was analysed during the inter-stimuli period and contrasted with a non-memory-related control task. The inter-stimulus memorization phase was characterized by a focal alpha-activity enhancement, significant during the nociceptive condition only, which progressed from bilateral occipital regions (cuneus and mid-occipital gyri) during the first encoding-memorization phase towards the right-superior and right mid-temporal gyri during the 2-4 s immediately preceding S2. Initial alpha enhancement in occipital areas/cuneus is consistent with rapid non-specific inhibition of task-irrelevant visual processing during initial stimulus encoding. Its transfer to the right-temporal regions was concomitant to the temporary upholding of the stimulus perceptual representation, previous to receiving S2, and suggests an active and local blockade of external interferences while these regions actively maintain internal information. These results add to a growing field indicating that alpha oscillations, while indicating local inhibitory processes, can also indirectly reveal active stimulus handling, including maintenance in short-term memory buffers, by objectivizing the filtering out of irrelevant and potentially disrupting inputs in brain regions engaged in internally driven operations.

Functional connectivity between medial pulvinar and cortical networks as a predictor of arousal to noxious stimuli during sleep.

The interruption of sleep by a nociceptive stimulus is favoured by an increase in the pre-stimulus functional connectivity between sensory and higher level cortical areas. In addition, stimuli inducing arousal also trigger a widespread electroencephalographic (EEG) response reflecting the coordinated activation of a large cortical network. Because functional connectivity between distant cortical areas is thought to be underpinned by trans-thalamic connections involving associative thalamic nuclei, we investigated the possible involvement of one principal associative thalamic nucleus, the medial pulvinar (PuM), in the sleeper's responsiveness to nociceptive stimuli. Intra-cortical and intra-thalamic signals were analysed in 440 intracranial electroencephalographic (iEEG) segments during nocturnal sleep in eight epileptic patients receiving laser nociceptive stimuli. The spectral coherence between the PuM and 10 cortical regions grouped in networks was computed during 5 s before and 1 s after the nociceptive stimulus and contrasted according to the presence or absence of an arousal EEG response. Pre- and post-stimulus phase coherence between the PuM and all cortical networks was significantly increased in instances of arousal, both during N2 and paradoxical (rapid eye movement [REM]) sleep. Thalamo-cortical enhancement in coherence involved both sensory and higher level cortical networks and predominated in the pre-stimulus period. The association between pre-stimulus widespread increase in thalamo-cortical coherence and subsequent arousal suggests that the probability of sleep interruption by a noxious stimulus increases when it occurs during phases of enhanced trans-thalamic transfer of information between cortical areas.

Amygdala and anterior insula control the passage from nociception to pain.

Activation of the spinothalamic system does not always result in a subjective pain perception. While the cerebral network processing nociception is relatively well known, the one underlying its transition to conscious pain remains poorly described. We used intracranial electroencephalography in epileptic patients to investigate whether the amplitudes and functional connectivity of posterior and anterior insulae (PI and AI) and amygdala differ according to the subjective reports to laser stimuli delivered at a constant intensity set at nociceptive threshold. Despite the constant intensity of stimuli, all patients reported variable subjective perceptions from one stimulus to the other. Responses in the sensory PI remained stable throughout the experiment, hence reflecting accurately the stability of the stimulus. In contrast, both AI and amygdala responses showed significant enhancements associated with painful relative to nonpainful reports, in a time window corresponding to the conscious integration of the stimulus. Functional connectivity in the gamma band between these two regions increased significantly, both before and after stimuli perceived as painful. While the PI appears to transmit faithfully the actual stimulus intensity received via the spinothalamic tract, the AI and the amygdala appear to play a major role in the transformation of nociceptive signals into a painful perception.

Joint European Academy of Neurology-European Pain Federation-Neuropathic Pain Special Interest Group of the International Association for the Study of Pain guidelines on neuropathic pain assessment.

BACKGROUND AND PURPOSE: In these guidelines, we aimed to develop evidence-based recommendations for the use of screening questionnaires and diagnostic tests in patients with neuropathic pain (NeP). METHODS: We systematically reviewed studies providing information on the sensitivity and specificity of screening questionnaires, and quantitative sensory testing, neurophysiology, skin biopsy, and corneal confocal microscopy. We also analysed how functional neuroimaging, peripheral nerve blocks, and genetic testing might provide useful information in diagnosing NeP. RESULTS: Of the screening questionnaires, Douleur Neuropathique en 4 Questions (DN4), I-DN4 (self-administered DN4), and Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) received a strong recommendation, and S-LANSS (self-administered LANSS) and PainDETECT weak recommendations for their use in the diagnostic pathway for patients with possible NeP. We devised a strong recommendation for the use of skin biopsy and a weak recommendation for quantitative sensory testing and nociceptive evoked potentials in the NeP diagnosis. Trigeminal reflex testing received a strong recommendation in diagnosing secondary trigeminal neuralgia. Although many studies support the usefulness of corneal confocal microscopy in diagnosing peripheral neuropathy, no study specifically investigated the diagnostic accuracy of this technique in patients with NeP. Functional neuroimaging and peripheral nerve blocks are helpful in disclosing pathophysiology and/or predicting outcomes, but current literature does not support their use for diagnosing NeP. Genetic testing may be considered at specialist centres, in selected cases. CONCLUSIONS: These recommendations provide evidence-based clinical practice guidelines for NeP diagnosis. Due to the poor-to-moderate quality of evidence identified by this review, future large-scale, well-designed, multicentre studies assessing the accuracy of diagnostic tests for NeP are needed.

Insular dichotomy in the implicit detection of emotions in human faces.

The functional roles of the insula diverge between its posterior portion (PI), mainly connected with somato-sensory and motor areas, and its anterior section (AI) connected with the frontal, limbic, and cingulate regions. We report intracranial recordings of local field evoked potentials from PI, AI, and the visual fusiform gyrus to a full array of emotional faces including pain while the individuals' attention was diverted from emotions. The fusiform gyrus and PI responded equally to all types of faces, including neutrals. Conversely, the AI responded only to emotional faces, maximally to pain and fear, while remaining insensitive to neutrals. The two insular sectors reacted with almost identical latency suggesting their parallel initial activation via distinct functional routes. The consistent responses to all emotions, together with the absence of response to neutral faces, suggest that early responses in the AI reflect the immediate arousal value and behavioral relevance of emotional stimuli, which may be subserved by "fast track" routes conveying coarse-spatial-frequency information via the superior colliculus and dorsal pulvinar. Such responses precede the conscious detection of the stimulus' precise signification and valence, which need network interaction and information exchange with other brain areas, for which the AI is an essentialhub.

Intracortical Functional Connectivity Predicts Arousal to Noxious Stimuli during Sleep in Humans.

Nociceptive stimuli disrupt sleep, but may, or may not, entail an arousal. While arousal reactions go along with the activation of a widespread cortical network, the factors enabling such activation remain unknown. Here we used intracranial EEG in humans to test the relation between the cortical activity immediately preceding a noxious stimulus and the capacity of such a stimulus to trigger arousal. Intracranial EEG signals were analyzed during all-night sleep in 14 epileptic patients (4 women), who received laser stimuli slightly above their individual pain threshold. During 5 s preceding each stimulus, the functional correlation (spectral phase-coherence) between the main spinothalamic sensory area (posterior insula) and 12 other brain regions, grouped in four networks, as well as their spectral contents, were contrasted according to the presence of a stimulus-induced arousal, and then fed into a logistic regression model to assess their predictive value. Enhanced prestimulus phase-coherence between the sensory posterior insula and neocortical and limbic areas increased significantly the probability of arousal to nociceptive stimuli, in both slow-wave (N2) and rapid eye movements/paradoxical sleep. Furthermore, during N2 sleep, arousal was facilitated by stimulus delivery in periods of attenuated slow-wave activity. Together, these data indicate that sleep micro-states with enhanced interareal communication facilitate information transfer from sensory to higher-order cortical areas, and hence physiological arousal.SIGNIFICANCE STATEMENT Sleep is commonly subdivided into stages based on specific electrophysiological characteristics; however, within each single sleep stage, the functional state of the brain is continuously changing. Here we show that the probability for a phasic noxious stimulus to entail an arousal is modulated by the prestimulus interareal phase-coherence between sensory and higher-level cortical areas. Fluctuations in interareal communication immediately before the noxious stimulus may determine the responsiveness to incoming input by facilitating or preventing the transfer of noxious information from sensory to multiple higher-level cortical networks.

Pharmacological Probes to Validate Biomarkers for Analgesic Drug Development.

There is an urgent need for analgesics with improved efficacy, especially in neuropathic and other chronic pain conditions. Unfortunately, in recent decades, many candidate analgesics have failed in clinical phase II or III trials despite promising preclinical results. Translational assessment tools to verify engagement of pharmacological targets and actions on compartments of the nociceptive system are missing in both rodents and humans. Through the Innovative Medicines Initiative of the European Union and EFPIA, a consortium of researchers from academia and the pharmaceutical industry was established to identify and validate a set of functional biomarkers to assess drug-induced effects on nociceptive processing at peripheral, spinal and supraspinal levels using electrophysiological and functional neuroimaging techniques. Here, we report the results of a systematic literature search for pharmacological probes that allow for validation of these biomarkers. Of 26 candidate substances, only 7 met the inclusion criteria: evidence for nociceptive system modulation, tolerability, availability in oral form for human use and absence of active metabolites. Based on pharmacokinetic characteristics, three were selected for a set of crossover studies in rodents and healthy humans. All currently available probes act on more than one compartment of the nociceptive system. Once validated, biomarkers of nociceptive signal processing, combined with a pharmacometric modelling, will enable a more rational approach to selecting dose ranges and verifying target engagement. Combined with advances in classification of chronic pain conditions, these biomarkers are expected to accelerate analgesic drug development.

Somatosensory Thalamic Activity Modulation by Posterior Insular Stimulation: Cues to Clinical Application Based on Comparison of Frequencies in a Cat Model.

BACKGROUND: The posterior insula (PI) has been proposed as a potential neurostimulation target for neuropathic pain relief as it represents a key-structure in pain processing. However, currently available data remain inconclusive as to efficient stimulation parameters. OBJECTIVE: As frequency was shown to be the most correlated parameter to pain relief, this study aims to evaluate the potential modulatory effects of low frequency (LF-IS, 50 Hz) and high-frequency (HF-IS, 150 Hz) posterior insular stimulation on the activity of somatosensory thalamic nuclei. MATERIALS AND METHODS: Epidural bipolar electrodes were placed over the PI of healthy adult cats, and extracellular single-unit activities of nociceptive (NS), nonnociceptive (NN), and wide dynamic range (WDR) thalamic cells were recorded within the ventral posterolateral nucleus and the medial division of the thalamic posterior complex. Mean discharge frequency and burst firing mode were analyzed before and after either LF-IS or HF-IS. RESULTS: LF-IS showed a significant thalamic modulatory effects increasing the firing rate of NN cells (p ≤ 0.03) and decreasing the burst firing of NS cells (p ≤ 0.03), independently of the thalamic nucleus. Conversely, HF-IS did not induce any change in firing properties of the three recorded cell types. CONCLUSION: These data indicate that 50 Hz IS could be a better candidate to control neuropathic pain.

Local sleep spindles in the human thalamus.

KEY POINTS: Sleep spindles have recently been shown to occur not only across multiple neocortical regions but also locally in restricted cortical areas. Here we show that local spindles are indeed present in the human posterior thalamus. Thalamic local spindles had lower spectral power than non-local ones. While non-local thalamic spindles had equal local and non-local cortical counterparts, local thalamic spindles had significantly more local cortical counterparts (i.e. occurring in a single cortical site). The preferential association of local thalamic and cortical spindles supports the notion of thalamocortical loops functioning in a modular way. ABSTRACT: Sleep spindles are believed to subserve many sleep-related functions, from memory consolidation to cortical development. Recent data using intracerebral recordings in humans have shown that they occur across multiple neocortical regions but may also be spatially restricted to specific brain areas (local spindles). The aim of this study was to characterize spindles at the level of the human posterior thalamus, with the hypothesis that, besides the global thalamic spindling activity usually observed, local spindles could also be present in the thalamus. Using intracranial, time-frequency EEG recordings in 17 epileptic patients, we assessed the distribution of thalamic spindles during natural sleep stages N2 and N3 in six thalamic nuclei. Local spindles (i.e. spindles present in a single pair of recording contacts) were observed in all the thalamic regions explored, and compared with non-local spindles in terms of intrinsic properties and cortical counterparts. Thalamic local and non-local spindles did not differ in density, frequency or duration, but local spindles had lower spectral power than non-local ones. Each thalamic spindle had a cortical counterpart. While non-local thalamic spindles had equal cortical local and non-local counterparts, local thalamic spindles had significantly more local cortical counterparts (i.e. occurring in a single cortical site). The preferential association of local thalamic and cortical spindles supports the notion of thalamocortical loops functioning in a modular way.

Insular-limbic dissociation to intra-epidermal electrical Aδ activation: A comparative study with thermo-nociceptive laser stimulation.

Intra-epidermal electrical stimulation (IEES) has been shown to activate selectively Aδ fibers subserving spinothalamic-mediated sensations. Owing to electrically induced highly synchronous afferent volleys, IEES induces Aδ-mediated evoked potentials at nonpainful intensities, contrasting with thermo-nociceptive laser pulses which entail painful pricking sensations. Here, we recorded intracortical responses from sensory and limbic-cognitive regions of human subjects in response to IEE and laser stimuli, in order to test the hypothesis that IEES could dissociate the sensory from nonsensory networks of nociceptive processing. Intracortical evoked potentials were obtained in 11 epileptic patients with stereotactically implanted electrodes in sensory regions receiving spinothalamic afferents (posterior insula), limbic regions receiving spino-parabrachial input (amygdalar nucleus), and high-order affective-cognitive regions (anteromedial frontal cortex, including perigenual anterior cingulate and rostromedial prefrontal areas). Responses in the sensory posterior insula were of similar amplitude and latency to IEE and laser stimuli (after accounting for heat-transduction time of laser), and consistent in both cases with spinothalamic activation. However, responses to IEES in the amygdala and the anteromedial frontal regions were inconsistent and significantly smaller compared to those evoked to the laser stimulation. Thus, IEES can effectively activate the spinothalamic-sensory system with little recruitment of affective-motivational networks, including those triggered by spino-parabrachio-amygdalar projections. The fact that identical sensory responses were associated to either painful or nonpainful percepts underscores that subjective pain perception is not solely dependent on the sensory recruitment, but rather on the combined activation of sensory, limbic and cognitive areas with precise spatiotemporal relations.

Evidence-based source modeling of nociceptive cortical responses: A direct comparison of scalp and intracranial activity in humans.

BACKGROUND: Source modeling of EEG traditionally relies on interplay between physiological hypotheses and mathematical estimates. We propose to optimize the process by using evidence gathered from brain imaging and intracortical recordings. METHODS: We recorded laser-evoked potentials in 18 healthy participants, using high-density EEG. Brain sources were modeled during the first second poststimulus, constraining their initial position to regions where nociceptive-related activity has been ascertained by intracranial EEG. These comprised the two posterior operculo-insular regions, primary sensorimotor, posterior parietal, anterior cingulate/supplementary motor (ACC/SMA), bilateral frontal/anterior insular, and posterior cingulate (PCC) cortices. RESULTS: The model yielded an average goodness of fit of 91% for individual and 95.8% for grand-average data. When compared with intracranial recordings from 27 human subjects, no significant difference in peak latencies was observed between modeled and intracranial data for 5 of the 6 assessable regions. Morphological match was excellent for operculo-insular, frontal, ACC/SMA and PCC regions (cross-correlation > 0.7) and fair for sensori-motor and posterior parietal cortex (c-c ∼ 0.5). CONCLUSIONS: Multiple overlapping activities evoked by nociceptive input can be disentangled from high-density scalp EEG guided by intracranial data. Modeled sources accurately described the timing and morphology of most activities recorded with intracranial electrodes, including those coinciding with the emergence of stimulus awareness. Hum Brain Mapp 38:6083-6095, 2017. © 2017 Wiley Periodicals, Inc.

Thalamic pain: anatomical and physiological indices of prediction.

Thalamic pain is a severe and treatment-resistant type of central pain that may develop after thalamic stroke. Lesions within the ventrocaudal regions of the thalamus carry the highest risk to develop pain, but its emergence in individual patients remains impossible to predict. Because damage to the spino-thalamo-cortical system is a crucial factor in the development of central pain, in this study we combined detailed anatomical atlas-based mapping of thalamic lesions and assessment of spinothalamic integrity using quantitative sensory analysis and laser-evoked potentials in 42 thalamic stroke patients, of whom 31 had developed thalamic pain. More than 97% of lesions involved an area between 2 and 7 mm above the anterior-posterior commissural plane. Although most thalamic lesions affected several nuclei, patients with central pain showed maximal lesion convergence on the anterior pulvinar nucleus (a major spinothalamic target) while the convergence area lay within the ventral posterior lateral nucleus in pain-free patients. Both involvement of the anterior pulvinar nucleus and spinothalamic dysfunction (nociceptive thresholds, laser-evoked potentials) were significantly associated with the development of thalamic pain, whereas involvement of ventral posterior lateral nucleus and lemniscal dysfunction (position sense, graphaesthesia, pallaesthesia, stereognosis, standard somatosensory potentials) were similarly distributed in patients with or without pain. A logistic regression model combining spinothalamic dysfunction and anterior pulvinar nucleus involvement as regressors had 93% sensitivity and 87% positive predictive value for thalamic pain. Lesion of spinothalamic afferents to the posterior thalamus appears therefore determinant to the development of central pain after thalamic stroke. Sorting out of patients at different risks of developing thalamic pain may be achievable at the individual level by combining lesion localization and functional investigation of the spinothalamic system. As the methods proposed here do not need complex manipulations, they can be added to routine patients' work up, and the results replicated by other investigators in the field.

Thalamic Responses to Nociceptive-Specific Input in Humans: Functional Dichotomies and Thalamo-Cortical Connectivity.

While nociceptive cortical activation is now well characterized in humans, understanding of the nociceptive thalamus remains largely fragmentary. We used laser stimuli and intracerebral electrodes in 17 human subjects to record nociceptive-specific field responses in 4 human thalamic nuclei and a number of cortical areas. Three nuclei known to receive spinothalamic (STT) projections in primates (ventro-postero-lateral [VPL], anterior pulvinar [PuA], and central lateral [CL]) exhibited responses with similar latency, indicating their parallel activation by nociceptive afferents. Phase coherence analysis, however, revealed major differences in their functional connectivity: while VPL and PuA drove a limited set of cortical targets, CL activities were synchronized with a large network including temporal, parietal, and frontal areas. Our data suggest that STT afferents reach simultaneously a set of lateral and medial thalamic regions unconstrained by traditional nuclear borders. The broad pattern of associated cortical networks suggests that a single nociceptive volley is able to trigger the sensory, cognitive, and emotional activities that underlie the complex pain experience. The medial pulvinar, an associative nucleus devoid of STT input, exhibited delayed responses suggesting its dependence on descending cortico-thalamic projections. Its widespread cortical connectivity suggests a role in synchronizing parietal, temporal, and frontal activities, hence contributing to the access of noxious input to conscious awareness.

Pain networks from the inside: Spatiotemporal analysis of brain responses leading from nociception to conscious perception.

Conscious perception of painful stimuli needs the contribution of an extensive cortico-subcortical network, and is completed in less than one second. While initial activities in operculo-insular and mid-cingulate cortices have been extensively assessed, the activation timing of most areas supporting conscious pain has barely been studied. Here we used intracranial EEG to investigate the dynamics of 16 brain regions (insular, parietal, prefrontal, cingulate, hippocampal and limbic) during the first second following nociceptive-specific laser pulses. Three waves of activation could be defined according to their temporal relation with conscious perception, ascertained by voluntary motor responses. Pre-conscious activities were recorded in the posterior insula, operculum, mid-cingulate and amygdala. Antero-insular, prefrontal and posterior parietal activities started later and developed during time-frames consistent with conscious voluntary reactions. Responses from hippocampus, perigenual and perisplenial cingulate developed latest and persisted well after conscious perception occurred. Nociceptive inputs reach simultaneously sensory and limbic networks, probably through parallel spino-thalamic and spino-parabrachial pathways, and the initial limbic activation precedes conscious perception of pain. Access of sensory information to consciousness develops concomitant to fronto-parietal activity, while late-occurring responses in the hippocampal region, perigenual and posterior cingulate cortices likely underlie processes linked to memory encoding, self-awareness and pain modulation. Hum Brain Mapp 37:4301-4315, 2016. © 2016 Wiley Periodicals, Inc.

Sleep spindles and human cortical nociception: a surface and intracerebral electrophysiological study.

KEY POINTS: Sleep spindle are usually considered to play a major role in inhibiting sensory inputs. Using nociceptive stimuli in humans, we tested the effect of spindles on behavioural, autonomic and cortical responses in two experiments using surface and intracerebral electroencephalographic recordings. We found that sleep spindles do not prevent arousal reactions to nociceptive stimuli and that autonomic reactivity to nociceptive inputs is not modulated by spindle activity. Moreover, neither the surface sensory, nor the insular evoked responses were modulated by the spindle, as detected at the surface or within the thalamus. The present study comprises the first investigation of the effect of spindles on nociceptive information processing and the results obtained challenge the classical inhibitory effect of spindles. ABSTRACT: Responsiveness to environmental stimuli declines during sleep, and sleep spindles are often considered to play a major role in inhibiting sensory inputs. In the present study, we tested the effect of spindles on behavioural, autonomic and cortical responses to pain, in two experiments assessing surface and intracerebral responses to thermo-nociceptive laser stimuli during the all-night N2 sleep stage. The percentage of arousals remained unchanged as a result of the presence of spindles. Neither cortical nociceptive responses, nor autonomic cardiovascular reactivity were depressed when elicited within a spindle. These results could be replicated in human intracerebral recordings, where sleep spindle activity in the posterior thalamus failed to depress the thalamocortical nociceptive transmission, as measured by sensory responses within the posterior insula. Hence, the assumed inhibitory effect of spindles on sensory inputs may not apply to the nociceptive system, possibly as a result of the specificity of spinothalamic pathways and the crucial role of nociceptive information for homeostasis. Intriguingly, a late scalp response commonly considered to reflect high-order stimulus processing (the 'P3' potential) was significantly enhanced during spindling, suggesting a possible spindle-driven facilitation, rather than attenuation, of cortical nociception.

Effects of aging on laser evoked potentials.

INTRODUCTION: Aging has been reported to reduce the amplitude of laser evoked potentials. However, it is unknown whether this effect depends on the length of the sensory fibers. This is an important issue, because most painful neuropathies are length-dependent. METHODS: We conducted a study of 40 healthy subjects, half of whom were older than age 50 years. Nociceptive stimuli were delivered to the feet and thighs using a CO2 laser stimulator. RESULTS: Detection and pain perception thresholds did not correlate with age. Latencies of N1, N2, and P2 correlated positively with age on the feet but not on the thighs, whereas the amplitude of N2-P2 decreased with age for both areas. CONCLUSIONS: The effects of aging on latencies may reflect a distal loss of peripheral inputs and a length-dependent de-synchronization of the ascending nociceptive volley. Additional changes in peripheral and central processes may explain the diffuse decrease of N2-P2 amplitudes observed with aging.

Third International Congress on Epilepsy, Brain, and Mind: Part 2.

Epilepsy is both a disease of the brain and the mind. Here, we present the second of two papers with extended summaries of selected presentations of the Third International Congress on Epilepsy, Brain and Mind (April 3-5, 2014; Brno, Czech Republic). Humanistic, biologic, and therapeutic aspects of epilepsy, particularly those related to the mind, were discussed. The extended summaries provide current overviews of epilepsy, cognitive impairment, and treatment, including brain functional connectivity and functional organization; juvenile myoclonic epilepsy; cognitive problems in newly diagnosed epilepsy; SUDEP including studies on prevention and involvement of the serotoninergic system; aggression and antiepileptic drugs; body, mind, and brain, including pain, orientation, the "self-location", Gourmand syndrome, and obesity; euphoria, obsessions, and compulsions; and circumstantiality and psychiatric comorbidities.

Asleep but aware?

Despite sleep-induced drastic decrease of self-awareness, human sleep allows some cognitive processing of external stimuli. Here we report the fortuitous observation in a patient who, while being recorded with intra-cerebral electrodes, was able, during paradoxical sleep, to reproduce a motor behaviour previously performed at wake to consciously indicate her perception of nociceptive stimulation. Noxious stimuli induced behavioural responses only if they reached the cortex during periods when mid-frontal networks (pre-SMA, pre-motor cortex) were pre-activated. Sensory responses in the opercular cortex and insula were identical whether the noxious stimulus was to evoke or not a motor behaviour; conversely, the responses in mid-anterior cingulate were specifically enhanced for stimuli yielding motor responses. Neuronal networks implicated in the voluntary preparation of movements may be reactivated during paradoxical sleep, but only if behavioural-relevant stimuli reach the cortex during specific periods of "motor awareness". These local activation appeared without any global sleep stage change. This observation opens the way to further studies on the currently unknown capacity of the sleeping brain to interact meaningfully with its environment.

Changes in sensory hand representation and pain thresholds induced by motor cortex stimulation in humans.

Shrinking of deafferented somatosensory regions after neural damage is thought to participate to the emergence of neuropathic pain, and pain-relieving procedures have been reported to induce the normalization of altered cortical maps. While repetitive magnetic stimulation (rTMS) of the motor cortex can lessen neuropathic pain, no evidence has been provided that this is concomitant to changes in sensory maps. Here, we assessed in healthy volunteers the ability of 2 modes of motor cortex rTMS commonly used in pain patients to induce changes in pain thresholds and plastic phenomena in the S1 cortex. Twenty minutes of high-frequency (20 Hz) rTMS significantly increased pain thresholds in the contralateral hand, and this was associated with the expansion of the cortical representation of the hand on high-density electroencephalogram source analysis. Neither of these effects were observed after sham rTMS, nor following intermittent theta-burst stimulation (iTBS). The superiority of 20-Hz rTMS over iTBS to induce sensory plasticity may reflect its better match with intrinsic cortical motor frequencies, which oscillate at around 20 Hz. rTMS-induced changes might partly counterbalance the plasticity induced by a nerve lesion, and thus substantiate the use of rTMS to treat human pain. However, a mechanistic relation between S1 plasticity and pain-relieving effects is far from being established.

Fractal Similarity of Pain Brain Networks.

The conscious perception of pain is the result of dynamic interactions of neural activities from local brain regions to distributed brain networks. Mapping out the networks of functional connections between brain regions that form and disperse when an experimental participant received nociceptive stimulations allow to characterize the pattern of network connections related to the pain experience.Although the pattern of intra- and inter-areal connections across the brain are incredibly complex, they appear also largely scale free, with "fractal" connectivity properties reproducing at short and long-time scales. Our results combining intracranial recordings and functional imaging in humans during pain indicate striking similarities in the activity and topological representation of networks at different orders of temporality, with reproduction of patterns of activation from the millisecond to the multisecond range. The connectivity analyzed using graph theory on fMRI data was organized in four sets of brain regions matching those identified through iEEG (i.e., sensorimotor, default mode, central executive, and amygdalo-hippocampal).Here, we discuss similarities in brain network organization at different scales or "orders," in participants as they feel pain. Description of this fractal-like organization may provide clues about how our brain regions work together to create the perception of pain and how pain becomes chronic when its organization is altered.